1. Field of the Invention
This invention relates to novel boron-gadolinium compounds, and to a method of conducting imaging processes and/or neutron capture therapy with boron-gadolinium compounds.
2. Description of the Related Art
Interest in the Neutron Capture Therapy (NCT) of cancer has increased tremendously in recent years. A number of compounds are already in preclinical or clinical trials in the U.S., Europe, Japan, and Australian. Most of these studies are based on the use of .sup.10 B as the neutron capture agent. Although .sup.10 B has certain advantages (e.g., versatile chemistry, cost-effectiveness, type of radiation generated upon neutron capture, etc.) over other potential neutron capture agents, there are also some problems. For example, the boron concentrations in tissues are difficult to measure and noninvasive determination of boron distribution in the body is very difficult. Additionally, boron compounds in general have given poor tumor to blood ratio in the past, with some notable exceptions.
Recently, reports have described the use of .sup.157 Gd compounds as neutron capture agents. Gadolinium-157 has a much larger cross-section for thermal neutrons than boron-10 (66 times larger), and some Gd complexes have been shown to give good tumor to blood and tumor to tissue ratios.
A significant property of .sup.157 Gd is that, being paramagnetic, it is a very good contrast agent for imaging by magnetic resonance. In fact, one Gd complex is already in clinical use as an MRI agent.
However, as in the case with boron-10, gadolinium-157 also has certain disadvantages as a neutron capture agent. The gadolinium complexes are less potent and can be more toxic due to the type of radiation (.gamma.-radiation) generated upon neutron capture.
Therefore, a combination of .sup.10 B and .sup.157 Gd might compensate each isotope's weaknesses and offer a better therapeutic method of treatment. A single agent incorporating both .sup.10 B and .sup.157 Gd may therefore provide not only the diagnostic capability of detecting the tumor, but at the same time a better means of destroying the tumor by both .sup.10 B-NCT and .sup.157 Gd-NCT.
NCT is based on the nuclear reaction produced when a neutron capture agent such as .sup.10 B or .sup.157 Gd isotope (localized in tumor tissues) is irradiated with low energy thermal neutrons. The radiation produced is capable of effecting selective destruction of tumor cells while sparing normal cells. The advantage of NCT is the fact that it is a binary system, capable of independent variation of control of the neutron capture agent and thermal neutrons.
While a number of nuclei have high cross section for thermal neutrons, most of the studies have been focused on the use of .sup.10 B as the neutron capture agent. It would therefore be an advance in the art, and is an object of this invention to provide NCT agents with both .sup.10 B and .sup.157 Gd in the same compound.
Boron-10 has a high cross-section (3838 barns) for thermal neutrons. The reaction products of .sup.10 B and thermal neutrons have short path length and the high linear energy transfer (LET) radiation (LET&gt;100 KeV/.mu.m) is deposited within the cell giving preferential destruction if the boron is localized in the tumor.
Another advantage of .sup.10 B is that the chemistry of boron is very versatile and a variety of boron compounds can be readily synthesized. However, the problems with boron compounds are: 1) most of the compounds studied so far give poor tumor to blood ratio, although there are notable exceptions, e.g., boronated porphyrins; 2) boron distribution in the body is difficult to determine without isolating the organs and tissue, and although .sup.11 B nmr has been used for imaging, it is not very sensitive; and 3) boron concentrations in the tumor are also difficult to determine.
Gadolinium-157 has a much larger cross section (66 times larger than .sup.10 B) for thermal neutrons than boron-10. Gadolinium compounds (due to the presence of unpaired electrons) have been used successfully for NMR imaging and the diethylenetriamine pentaacetic acid complex of Gd.sup.3+ is currently undergoing clinical trials as an imaging agent. Gd compounds have been shown to provide high tumor concentrations and good tumor to tissue and tumor to blood ratios.
Many Gd complexes behave similar to the corresponding technetium complexes. Therefore, by substituting .sup.99m Tc for Gd along with the Gd complex, and by determining the concentration of technetium in various tissues, the concentration of Gd can be estimated. Alternatively, Gd concentrations in various tissues may be determined indirectly by measuring proton relaxivities (MRI).
The disadvantages of Gd are, however, that the major cell killing component of the radiation produced from Gd.sup.157 and neutron reaction is Auger electrons. To be effective these Auger e's have to be released in the vicinity of the genetic material and this constraint limits the effectiveness of Gd NCT in comparison to .sup.10 B-NCT. A second drawback of the .sup.157 Gd NCT is that a second component of radiation from .sup.157 Gd-neutron reaction, low LET gamma rays, are not only less effective in killing cells but can also travel longer distances and can destroy normal tissue. On the other hand, delivery of radiation to the surrounding tissue may increase the chance of hitting all the cells in the tumor. Thus a combination of boron-10 and gadolinium-157 may require lower concentration of each component (and decrease side effects) and still be more effective than each individual component at a higher concentration.
Concerning desirable characteristics for imaging reagents generally, the basic properties of good magnetic resonance imaging agents are as follows:
1) Relaxivity: The relaxivity of metal complexes (efficiency with which a complex enhances proton relaxation rate of water) should be sufficiently high. However, an increase of as little as 10-20% in 1/T.sub.1 could be detected by NMR imaging. Relaxivity may be increased by providing one or more inner sphere coordination site(s) for water molecules. PA1 2) Specificity: For NMR imaging agents it is important that the agent enhances the relaxation rates of target tissue in preference to other tissues. This may be accomplished either by preferential incorporation of compound or by difference in relaxivity if the complex has a higher relaxivity in the environment of one tissue over others. PA1 3) in vivo stability, lack of toxicity and rapid excretability: It is extremely important that the imaging agent has a low acute and chronic toxicity. Many complexes, while inherently nontoxic, could exhibit high toxicity upon dissociation into the free metal ions and ligands. Therefore, both the thermodynamic and the kinetic stabilities of complexes are very important. Additionally, after serving their purpose, diagnostic agents should be excreted within hours of administration. Of course, retention in tumor is highly desirable for NCT. PA1 4) Solubility in water: For ease of delivery, the imaging agent should have good solubility in water. PA1 5) Osmolality: Although not essential, it is beneficial to have uncharged species to prevent hyperosmolality with respect to body fluids. PA1 1) High cross-section for thermal neutrons: As indicated earlier, both .sup.10 B and .sup.157 Gd have high cross-section for thermal neutrons. PA1 2) Tumor specificity: In order for NCT to be effective, the neutron capture agent should preferentially localize into tumor cells. The position inside the cell is also important. So far, this has been one of the most challenging problems for NCT. PA1 3) Stability, Excretability and lack of toxicity: The same criteria apply here as for imaging agents. Not only should the compound have good stability and low toxicity after the treatment (or even before neutron capture reaction), the compound should also be readily excreted from the normal tissue of the body, but retained in tumor cells. PA1 R.sub.1, R.sub.2, and R.sub.3 are independently selected from carboxyl, carboxylic salt groups, carboxylic ester groups, and carboxylate anion; PA1 R.sub.4 is a boron-containing group; and PA1 x is a number from zero to 4. PA1 R.sub.4 is a boron-containing group; and PA1 x is a number from zero to 4. PA1 1,4,7-tris (carboxymethyl)-10-(1-carboranylpropyl)-1,4,7,10-tetraazacyclododecane PA1 1,4,7-tris (carboxymethyl)-10-(1-phenylpropyl)-1,4,7,10-tetraazacyclododecane PA1 R.sub.1, R.sub.2, and R.sub.3 are independently selected from carboxyl, carboxylic salt groups, carboxylic ester groups, and carboxylate anion; PA1 R.sub.4 is a boron-containing group; and PA1 x is a number from zero to 4. PA1 R.sub.1, R.sub.2, and R.sub.3 are independently selected from carboxyl, carboxylic salt groups, carboxylic ester groups, and carboxylate anion; PA1 R.sub.4 is a boron-containing group; and PA1 x is a number from zero to 4. PA1 R.sub.4 is a boron-containing group; and PA1 x is a number from zero to 4.
Considering the desired properties of NCT reagent materials, the properties of good NCT agents are as follows:
In addition, the criteria of good water solubility and low osomality also apply to NCT agents.
Accordingly, it is one object of the present invention to provide novel boron-gadolinium compounds having utility for imaging applications such as MRI as well as for NCT.
It is another object of the invention to provide a method of making such boron-gadolinium compounds.
It is a further object of the invention to provide a method of and compounds for contemporaneously conducting imaging and NCT processes, utilizing a single reagent formulation.
Other objects and intents of the present invention will be more fully apparent from the ensuing disclosure and appended claims.